[VIRTUAL] Identification of pathways that enhance cell death in NOTCH1-mutant HNSCC (AACR 2021)
We combined the resulting 74 drugs with PI3K inhibitors, bimiralisib (0-1µM) or copanlisib (FDA approved, 0-100nM), for 72 h. Synergistic effects from these combinations were assessed using Bliss, HAS, Zip, and Loewe models. Trametinib (MEK inhibitor) and copanlisib were synergistic with the combination leading to 0.90 fraction of cells affected at concentrations of 30nM and 100nM respectively...Likewise, low concentrations of inhibitors of EGFR (10nM afatinib, 50nM AZ5104), HER2 (25nM sapitinib, 10nM poziotinib), and PLK1 (50nM BI2536, 50nM volasertib) were both effective and additive to synergistic with PI3K inhibitors...The identified pathways may give us insight into mechanisms of resistance. If validated, these combinations may lead to the first biomarker-specific, targeted therapy for HNSCC.